The present studies in rats have further characterized the natural killer (NK) cell system in rats. Results using a wide variety of target cells have shown that the naturally cytotoxic effector cells for normal fibroblasts and bone marrow targets, lymphomas/leukemias, embryonic cell lines, and solid tumor targets are all included in the large granular lymphocyte (LGL) subpopulation, further emphasizing the importance of these cells as an antitumor effector mechanism. In addition, immunocytochemical localization of LGL in incidental and pathological lesions, and in lymphoid and nonlymphoid tissues of nude rats suggests that these cells play a role in the first lines of defense against not only tumors but also infectious agents. Other studies with the transplantable LGL leukemias in F344 rats have demonstrated a great deal of similarity with normal LGL, including similar cell surface antigens, histochemistry, and functional activity against NK-susceptible/resistant target cells. A number of similarities were noted between these LGL tumors and some previously reported cases of human TGamma-CLL. Further biochemical analysis of the rat LGL leukemias has resulted in the isolation of cytoplasmic granules which contain highly cytolytically active material(s). Further analysis of these molecules should help to elucidate the lytic mechanism of NK cells.